2 - TI Pharma

oral), the vulnerability of the population exposed [44] and the different stable isotope dilution
protocols that were employed to quantify EGP, may explain these seemingly contrasting
results. GC-induced increments in EGP in the basal state seem to be driven by increased GNG,
through a number of proposed mechanisms. First, GCs were shown to induce the expression
of rate limiting enzymes of GNG, including phosphoenolpyruvate carboxykinase (PEPCK)
and glucose-6-phosphatase (G6Pase), both in vitro and in vivo in rats [49-51]. Indeed, the
PEPCK gene contains a glucocorticoid response element (GRE) in its promoter region and is
considered a key player in GC-induced hyperglycemia [43]. Second, long-term GC-exposure
promotes breakdown of protein and fat stores [52], thus increasing the supply of substrates
for GNG, such as alanine and glycerol, to the liver [53]. As such, increased proteolysis was
shown to contribute to augmented GNG in obese nondiabetic subjects, in whom enhanced
skeletal muscle GC sensitivity has been reported [54], as compared to lean controls [55].
Third, GCs facilitate metabolite transport across the mitochondrial membranes in rat liver,
which enhances GNG [1,53]. Fourth, GCs might potentiate the effects of other glucoregulatory
hormones, such as glucagon and epinephrine, thus further enhancing EGP [52,56]. Finally,
a role for the nuclear receptor peroxisome proliferator-activated receptor (PPAR)-alpha
in GC-induced hepatic insulin resistance and hyperglycemia has recently been confirmed
[57,58]. PPAR-α, which is predominantly expressed in the liver and is the receptor for
the hypolipidemic fibrates, acts as a fatty acid sensor and is a major regulator of energy
homeostasis by promoting fatty acid oxidation, GNG and ketogenesis [59]. It was elegantly
demonstrated in PPAR-α knock out mice that PPAR-α expression is necessary for GC-induced
increases in EGP [57], and that the autonomous nervous system plays a key role [58].
The importance of the hepatic GC-GR axis in regulating EGP was additionally demonstrated
in transgenic mice with a liver-specific inactivation of the GR. These mice developed
hypoglycemia after prolonged fasting due to impaired activity of gluconeogenic enzymes [60].
3.2. Glucocorticoids alter hepatic lipid metabolism
In addition to regulating hepatic carbohydrate metabolism, insulin plays a key role in
hepatic lipid metabolism. In the postprandial state, portal insulin stimulates lipogenesis and
lipoprotein synthesis, whereas it suppresses very low-density lipoprotein (VLDL) secretion
[61]. GCs induce hepatic insulin resistance, both by direct interference with insulin signaling
and indirectly, by elevating plasma NEFA and TG supply to the liver [61]. GC-induced changes
in hepatic lipid metabolism may induce hepatic steatosis and dyslipidemia in humans,
although the currently available data are not conclusive.
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Chapter 2